X-linked adrenoleukodystrophy (ALD), which is the most common peroxisomal disorder, causes serious and often fatal damage to the nervous system. The adrenal cortex and testis are also affected. The disorder is characterized by the accumulation of very long chain fatty acids (VLCFA) due to the impaired capacity to degrade these substances, which are normally oxidized in the peroxisome; the gene has been mapped to Xq28. Although two forms of potential therapy have recently been examined, dietary intervention to reduce these levels of VLCFA, and bone marrow transplantation, evaluation of these is hampered by striking intrafamilial variability of ALD (from the always fatal cerebral childhood form, to the milder adolescent and adult forms, and still milder forms affecting only the adrenal). Because our laboratory has developed a diagnostic plasma assay for VLCFA and has access to multiple kindreds with various forms of ALD (1400 patients belonging to 615 kindreds have been identified), this project has two main objectives: Specific Aim 1 is designed to obtain data on the relative frequency and natural history of each of the phenotypes, by methods that will minimize ascertainment bias. This information is essential for counseling and for the evaluation of therapeutic interventions. The second major objective is to determine the cause of the intrafamilial phenotypic variability. Pedigree analysis suggests a genetic basis and our hypothesis is that it may be due to the action of a second gene that influences the expression of the primary gene defect. The capacity to determine genotype with certainty, the bimodal distribution of two most common and readily distinguishable phenotypes, and our access to many multiplex kindreds facilitate the test of this hypothesis. Identification of a modifier gene would be of general biological general interest and may help the design of therapy.